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Nivolumab in Combination With Metronomic Chemotherapy in Paediatrics Refractory / Relapsing Solid Tumors or Lymphoma

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ClinicalTrials.gov Identifier: NCT03585465
Recruitment Status : Not yet recruiting
First Posted : July 13, 2018
Last Update Posted : July 13, 2018
Sponsor:
Collaborators:
Anticancer Fund, Belgium
Bristol-Myers Squibb
Information provided by (Responsible Party):
Centre Oscar Lambret

Brief Summary:

The study is a two-stage trial:

  1. First stage : Phase I feasibility trial to evaluate the safety of the combination of Nivolumab + metronomic chemotherapy considering three possible metronomic chemotherapy regimens
  2. Second stage: Phase II randomized controlled balanced 1:1 open- label trial comparing the efficacy of the metronomic chemotherapy regimen selected at the end of the previous stage, with or without nivolumab.

Condition or disease Intervention/treatment Phase
Childhood Solid Tumor Childhood Lymphoma Drug: Vinblastine Drug: Cyclophosphamide Drug: Capecitabine Drug: Nivolumab Phase 1 Phase 2

Detailed Description:
  1. First stage :

    • Arm A: Nivolumab + Cyclophosphamide-Vinblastine
    • Arm B: Nivolumab + Capecitabin
    • Arm C: Nivolumab + Cyclophosphamide-Vinblastine + Capecitabin Arm A and Arm B will be initially allocated sequentially (A/B/A/B/A/B). Arm C will be opened, if arm A and Arm B are deemed safe. In each arm, the second patient will not be recruited before the first patient has been observed for a 28-day duration.
  2. Second stage will start after a meeting of IDMC Randomization will be balanced 1:1, controlling for histological type (HGG-Midline diffuse glioma / Lymphoma / Other) and treating center, using a dynamic allocation of treatment (minimization program) with a random factor set at 0.8.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Metro-PD1: a Phase I/II Trial Evaluating Anti-PD1 (Nivolumab) in Combination With Metronomic Chemotherapy in Children and Teenagers With Refractory / Relapsing Solid Tumors or Lymphoma
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : January 2024
Estimated Study Completion Date : July 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: A: Cyclophosphamide Vinblastine Nivolumab
First stage
Drug: Vinblastine
  • Experimentals Arm A or C (First stage): 2 mg/m2/day IV, weekly per cycle, 28 days cycle
  • Experimental Arms Metronomic or Metronomic+Nivolumab (second stage): see A or C

Drug: Cyclophosphamide
  • Arm A (First stage): 30 mg/m2/day PO, D1-4// D8-11// D15-18// D22-25 per cycle, 28 days cycle
  • Arm C (First stage): 30 mg/m2/day PO, D1-D4// D15-D18 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see A or C

Drug: Nivolumab
  • Arm A, B or C (First stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle
  • Metronomic+Nivolumab Arm (second stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle

Experimental: B: Capecitabine Nivolumab
First stage
Drug: Capecitabine
  • Arm B (First stage): 400 to 600 mg/m2/day PO, all days per cycle, 28 days cycle
  • Arm C (First stage): 400 to 600 mg/m2/day PO, D8-D11// D22-D25 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see B or C

Drug: Nivolumab
  • Arm A, B or C (First stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle
  • Metronomic+Nivolumab Arm (second stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle

Experimental: C: Cyclophosphamide Vinblastine Capecitabine
First stage
Drug: Vinblastine
  • Experimentals Arm A or C (First stage): 2 mg/m2/day IV, weekly per cycle, 28 days cycle
  • Experimental Arms Metronomic or Metronomic+Nivolumab (second stage): see A or C

Drug: Cyclophosphamide
  • Arm A (First stage): 30 mg/m2/day PO, D1-4// D8-11// D15-18// D22-25 per cycle, 28 days cycle
  • Arm C (First stage): 30 mg/m2/day PO, D1-D4// D15-D18 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see A or C

Drug: Capecitabine
  • Arm B (First stage): 400 to 600 mg/m2/day PO, all days per cycle, 28 days cycle
  • Arm C (First stage): 400 to 600 mg/m2/day PO, D8-D11// D22-D25 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see B or C

Drug: Nivolumab
  • Arm A, B or C (First stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle
  • Metronomic+Nivolumab Arm (second stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle

Experimental: Metronomic Arm (Second stage)
Arm retained at first stage (A, B or C)
Drug: Vinblastine
  • Experimentals Arm A or C (First stage): 2 mg/m2/day IV, weekly per cycle, 28 days cycle
  • Experimental Arms Metronomic or Metronomic+Nivolumab (second stage): see A or C

Drug: Cyclophosphamide
  • Arm A (First stage): 30 mg/m2/day PO, D1-4// D8-11// D15-18// D22-25 per cycle, 28 days cycle
  • Arm C (First stage): 30 mg/m2/day PO, D1-D4// D15-D18 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see A or C

Drug: Capecitabine
  • Arm B (First stage): 400 to 600 mg/m2/day PO, all days per cycle, 28 days cycle
  • Arm C (First stage): 400 to 600 mg/m2/day PO, D8-D11// D22-D25 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see B or C

Experimental: Metronomic + Nivolumab Arm (Second stage)
Nivolumab + Arm retained at the end of first stage (A, B or C)
Drug: Vinblastine
  • Experimentals Arm A or C (First stage): 2 mg/m2/day IV, weekly per cycle, 28 days cycle
  • Experimental Arms Metronomic or Metronomic+Nivolumab (second stage): see A or C

Drug: Cyclophosphamide
  • Arm A (First stage): 30 mg/m2/day PO, D1-4// D8-11// D15-18// D22-25 per cycle, 28 days cycle
  • Arm C (First stage): 30 mg/m2/day PO, D1-D4// D15-D18 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see A or C

Drug: Capecitabine
  • Arm B (First stage): 400 to 600 mg/m2/day PO, all days per cycle, 28 days cycle
  • Arm C (First stage): 400 to 600 mg/m2/day PO, D8-D11// D22-D25 per cycle, 28 days cycle
  • Metronomic or Metronomic+Nivolumab Arm (second stage): see B or C

Drug: Nivolumab
  • Arm A, B or C (First stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle
  • Metronomic+Nivolumab Arm (second stage): 3 mg/kg IV, D1 & D15 per cycle, 28 days cycle




Primary Outcome Measures :
  1. Dose Limiting Toxicities according to the NCI-CTCAE V5 [ Time Frame: Over the first chemotherapy cycle (28 days) ]
    First Stage Primary Outcome 3 metronomic CT are : A:Cyclophosphamide + Vinblastine B:Capecitabin C:Cyclophosphamide + Vinblastine + Capecitabin

  2. Progression-free survival according appropriate criteria (RANO, WHO, INRC, RECIST v1.1, or standard criteria for lymphoma). [ Time Frame: up to 2 years ]
    Second Stage Primary Outcome Metronomic chemotherapy is the same as regimen selected at the end of the first stage


Secondary Outcome Measures :
  1. Adverse events according to the NCI-CTCAE V5. [ Time Frame: up to 2 years ]
    First Stage Secondary Outcome & Second Stage Secondary Outcome 1

  2. Tumor response in terms of complete/partial response or stable/progressive disease (using RANO, WHO, INRC, RECIST v1.1, or standard criteria for lymphoma) and overall survival [ Time Frame: up to 2 years ]
    Second Stage Secondary Outcome 2

  3. Dose-intensity for each drug (ratio between the computed dose-intensity, and the protocol dose-intensity) [ Time Frame: up to 2 years ]
    Second Stage Secondary Outcome 3



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • Histologically proven diagnosis of solid malignant tumor, or lymphoma. Confirmed progressive or refractory disease despite standard therapy or for which no effective standard therapy exists
  • Male and female subjects > 4 to < 18 years of age at inclusion; patients 18 years and older may be included after discussion with the sponsor if they had a pediatric recurrent/refractory malignancy diagnosed before the age of 18.
  • Evaluable or measurable disease as defined by adequate standard imaging criteria for each patient's tumor type (see corresponding appendices for definition of evaluable and/or measurable lesions):

    • RANO criteria for patients with high grade glioma (HGG or midline diffuse glioma, see appendix 3),
    • WHO for other cerebral tumors (appendix 4)
    • INRC criteria for patients with neuroblastoma (NB, see appendix 5),
    • RECIST v1.1 for tumors other than cerebral tumors and neuroblastoma (appendix 6)
    • Standard response criteria for lymphoma (depending on lymphoma type),
  • Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Life expectancy ≥ 3 months
  • Adequate organ function:
  • Hematologic criteria - Peripheral absolute neutrophil count (ANC) ≥ 1500/mm3 (unsupported)
  • White blood cells count ≥ 2500/mm3
  • Platelet count ≥ 100,000/mm3 (unsupported)
  • Hemoglobin ≥ 8.0 g/dL (transfusion is allowed)
  • Cardiac function - Shortening fraction (SF) >29% (>35% for children < 3 years) and left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy). - Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia.
  • Renal and hepatic function - Serum creatinine < 1.5 x upper limit of normal (ULN) for age
  • Total bilirubin < 1.5 x ULN,
  • Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) < 3 x ULN;
  • aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT < 3 x ULN
  • Able to comply with scheduled follow-up and with management of toxicity.
  • Females of child bearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
  • Sexually active patients must agree to use adequate and appropriate contraception while on study drug and for 6 months after stopping the study drug.
  • Patient able to comfortably swallow capsules.
  • Patients on stable doses of corticosteroids (≤0.25 mg/kg prednisolone or equivalent) for at least 7 days prior to receiving study drug may be included.
  • Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
  • Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
  • Patients can have received prior treatment with antiPD1 or antiPDL1 if at least SD for 6 months or PR or CR was obtained.

EXCLUSION CRITERIA:

  • Any hematopoietic neoplasm
  • Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
  • Patients requiring high doses of corticosteroids >0.25mg/kg prednisolone or equivalent) or increasing doses of corticosteroids during the 7 days prior to receiving study drug.
  • For patients with CNS tumor:

    o Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.

    o Participants with bulky tumor on imaging are ineligible; bulky tumor is defined as: i) Tumor with any evidence of uncal herniation or severe midline shift ii) Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI iii) Tumor that in the opinion of the investigator, shows significant mass effect

  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  • Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening)
  • Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
  • Active autoimmune disease requiring immunosuppressive treatment
  • Known congenital immunodeficiency
  • Presence of any NCI-CTCAE v5 grade ≥ 2 treatment-related extra-hematological toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy.
  • Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less, 6 weeks in case of nitrosourea.
  • No clinical benefit with previous antiPD1 or antiPDL1 treatment (SD during a period inferior to 6 months, or PD).
  • Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose.
  • Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
  • Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
  • Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered.
  • Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
  • Known hypersensitivity to any study drug or component of the formulation.
  • Absence of effective contraception in patients of childbearing age
  • Pregnant or nursing (lactating) females.
  • Vaccination with live, attenuated vaccines within 4 weeks of the first dose of the study drugs except inactivated vaccines.
  • Known absence of dihydro-pyrimidine-deshydrogenase (DPD) activity; although a DPD deficiency can't be precisely defined, it is known that patients carrying some homozygous or heterozygous mutations of DPYD responsible for the complete or almost complete absence of enzymatic activity of DPD, are exposed to a maximum risk of life-threatening or fatal toxicity and should not be treated with capecitabine
  • Patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases)
  • Acute urinary tract infection, pre-existing hemorrhagic cystitis; obstruction of the urinary tract

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03585465


Contacts
Contact: Alicia PROBST +33320295918 promotion@o-lambret.fr

Sponsors and Collaborators
Centre Oscar Lambret
Anticancer Fund, Belgium
Bristol-Myers Squibb
Investigators
Study Director: Pierre LEBLOND, MD Centre Oscar Lambret
Study Director: Nicolas ANDRE, MD CHU La Timone

Responsible Party: Centre Oscar Lambret
ClinicalTrials.gov Identifier: NCT03585465     History of Changes
Other Study ID Numbers: Metro-PD1-1708
First Posted: July 13, 2018    Key Record Dates
Last Update Posted: July 13, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Nivolumab
Capecitabine
Vinblastine
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators